Facilitating participation in adults with and without vision loss by supporting exhibit motivations through real-time descriptive mediation

Design and evaluation of real-time descriptive mediation (RTDM) for live aquarium exhibits was proposed to support the participation of visitors with and without vision loss. RTDM was developed to address learning, entertainment, restorative, and social motivations. Data was collected during a lab study with adults to get feedback about the RTDM and compare it to traditional docent presentations and audio tours. Findings show that the RTDM made it possible for participants to address their exhibit motivations and led to specific personal and social aspects of participation. A majority of participants with and without vision loss reported that the RTDM was supportive of their motivations and perceived it to be more effective at supporting learning, social, and restoration motivations compared to audio tour and docent mediation. The main contributions of this work are in: 1) developing evidence-based information design criteria for mediation at live animal exhibits; 2) demonstrating that mediation designed to support exhibit motivations can facilitate participation in adults with and without vision loss; and 3) validating participation as a design goal.Ph.D

Sonification Mapping Configurations: Pairings Of Real-Time Exhibits And Sound

Presented at the 19th International Conference on Auditory Display (ICAD2013) on July 6-9, 2013 in Lodz, Poland.Visitors to aquariums typically rely on their vision to interact with live exhibits that convey rich descriptive and aesthetic visual information. However, some visitors may prefer or need to have an alternative interpretation of the exhibitÕs visual scene to improve their experience. Musical sonification has been explored as an interpretive strategy for this purpose and related work provides some guidance for sonification design, yet more empirical work on developing and validating the music-to-visual scene mappings needs to be completed. This paper discusses work to validate mappings that were developed through an investigation of musician performances for two specific live animal exhibits at the Georgia Aquarium. In this proposed study, participants will provide feedback on musical mapping examples which will help inform design of a real-time sonification system for aquarium exhibits. Here, we describe our motivation, methods, and expected contributions

A phage-targeting strategy for the design of spatiotemporal drug delivery from grafted matrices

Abstract Background The natural response to injury is dynamic and normally consists of complex temporal and spatial cellular changes in gene expression, which, when acting in synchrony, result in patent tissue repair and, in some instances, regeneration. However, current therapeutic regiments are static and most rely on matrices, gels and engineered skin tissue. Accordingly, there is a need to design next-generation grafting materials to enable biotherapeutic spatiotemporal targeting from clinically approved matrices. To this end, rather then focus on developing completely new grafting materials, we investigated whether phage display could be deployed onto clinically approved synthetic grafts to identify peptide motifs capable of linking pharmaceutical drugs with differential affinities and eventually, control drug delivery from matrices over both space and time. Methods To test this hypothesis, we biopanned combinatorial peptide libraries onto different formulations of a wound-healing matrix (Integra®) and eluted the bound peptides with 1) high salt, 2) collagen and glycosaminoglycan or 3) low pH. After three to six rounds of biopanning, phage recovery and phage amplification of the bound particles, any phage that had acquired a capacity to bind the matrix was sequenced. Results In this first report, we identify distinct classes of matrix-binding peptides which elute differently from the screened matrix and demonstrate that they can be applied in a spatially relevant manner. Conclusions We suggest that further applications of these combinatorial techniques to wound-healing matrices may offer a new way to improve the performance of clinically approved matrices so as to introduce temporal and spatial control over drug delivery

A Mechanism Misregulating p27 in Tumors Discovered in a Functional Genomic Screen

The cyclin-dependent kinase inhibitor p27KIP1 is a tumor suppressor gene in mice, and loss of p27 protein is a negative prognostic indicator in human cancers. Unlike other tumor suppressors, the p27 gene is rarely mutated in tumors. Therefore misregulation of p27, rather than loss of the gene, is responsible for tumor-associated decreases in p27 protein levels. We performed a functional genomic screen in p27+/− mice to identify genes that regulate p27 during lymphomagenesis. This study demonstrated that decreased p27 expression in tumors resulted from altered transcription of the p27 gene, and the retroviral tagging strategy enabled us to pinpoint relevant transcription factors. inhibitor of DNA binding 3 (Id3) was isolated and validated as a transcriptional repressor of p27. We further demonstrated that p27 was a downstream target of Id3 in src-family kinase Lck-driven thymic lymphomagenesis and that p27 was an essential regulator of Lck-dependent thymic maturation during normal T-cell development. Thus, we have identified and characterized transcriptional repression of p27 by Id3 as a new mechanism decreasing p27 protein in tumors

Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics

Derepression of DUX4 in skeletal muscle has emerged as a likely cause of pathology in facioscapulohumeral muscular dystrophy (FSHD). Here we report on the use of antisense phosphorodiamidate morpholino oligonucleotides to suppress DUX4 expression and function in FSHD myotubes and xenografts. The most effective was phosphorodiamidate morpholino oligonucleotide FM10, which targets the polyadenylation signal of DUX4. FM10 had no significant cell toxicity, and RNA-seq analyses of FSHD and control myotubes revealed that FM10 down-regulated many transcriptional targets of DUX4, without overt off-target effects. Electroporation of FM10 into FSHD patient muscle xenografts in mice also down-regulated DUX4 and DUX4 targets. These findings demonstrate the potential of antisense phosphorodiamidate morpholino oligonucleotides as an FSHD therapeutic option

Bacterial Pneumonias during an Influenza Pandemic: How Will We Allocate Antibiotics?

We are currently in the midst of the 2009 H1N1 pandemic, and a second wave of flu in the fall and winter could lead to more hospitalizations for pneumonia. Recent pathologic and historic data from the 1918 influenza pandemic confirms that many, if not most, of the deaths in that pandemic were a result of secondary bacterial pneumonias. This means that a second wave of 2009 H1N1 pandemic influenza could result in a widespread shortage of antibiotics, making these medications a scarce resource. Recently, our University of Michigan Health System (UMHS) Scarce Resource Allocation Committee (SRAC) added antibiotics to a list of resources (including ventilators, antivirals, vaccines) that might become scarce during an influenza pandemic. In this article, we summarize the data on bacterial pneumonias during the 1918 influenza pandemic, discuss the possible impact of a pandemic on the University of Michigan Health System, and summarize our committee's guiding principles for allocating antibiotics during a pandemic.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78141/1/bsp.2009.0019.pd

Mechanisms of drug-induced lupus. III. Sex-specific differences in T cell homing may explain increased disease severity in female mice

Objective . To determine if sex-specific differences in lymphocyte trafficking could contribute to increased disease severity in female mice. Methods . A lupus-like disease was induced by injecting male and female mice with procainamide-treated T cell clones. Trafficking was examined by labeling the injected cells with 51 Cr or 5-chloromethylfluorescein diacetate. Results . Females developed more autoimmune liver disease and greater titers of anti-DNA antibodies than did males, and 2-7 times more cells accumulated in the female spleens. Splenectomy prevented the development of autoantibodies and renal and liver disease. Oophorectomy decreased the splenic homing, autoantibody titer, and liver disease severity, to levels found in males. Conclusion . T cells traffic differently to the spleen in male and female mice, and the spleen appears to be essential in the disease process. This suggests that differences in T cell homing could contribute to sex-specific disease severity in this murine model, and also possibly in human disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/37813/1/1780400719_ftp.pd

Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA

Primary pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of surfactant in the lungs that is presumed to be mediated by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling based on studies in genetically modified mice. The effects of GM-CSF are mediated by heterologous receptors composed of GM-CSF binding (GM-CSF-Rα) and nonbinding affinity-enhancing (GM-CSF-Rβ) subunits. We describe PAP, failure to thrive, and increased GM-CSF levels in two sisters aged 6 and 8 yr with abnormalities of both GM-CSF-Rα–encoding alleles (CSF2RA). One was a 1.6-Mb deletion in the pseudoautosomal region of one maternal X chromosome encompassing CSF2RA. The other, a point mutation in the paternal X chromosome allele encoding a G174R substitution, altered an N-linked glycosylation site within the cytokine binding domain and glycosylation of GM-CSF-Rα, severely reducing GM-CSF binding, receptor signaling, and GM-CSF–dependent functions in primary myeloid cells. Transfection of cloned cDNAs faithfully reproduced the signaling defect at physiological GM-CSF concentrations. Interestingly, at high GM-CSF concentrations similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow progression of disease in these children. These results establish that GM-CSF signaling is critical for surfactant homeostasis in humans and demonstrate that mutations in CSF2RA cause familial PAP

Outcome of transplantation for acute lymphoblastic leukemia in children with down syndrome

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106900/1/pbc24918.pd

Outcome of Transplantation for Acute Myelogenous Leukemia in Children with Down Syndrome

AbstractData on outcomes of allogeneic transplantation in children with Down syndrome and acute myelogenous leukemia (DS-AML) are scarce and conflicting. Early reports stress treatment-related mortality as the main barrier; a recent case series points to posttransplantation relapse. We reviewed outcome data for 28 patients with DS-AML reported to the Center for International Blood and Marrow Transplant Research between 2000 and 2009 and performed a first matched-pair analysis of 21 patients with DS-AML and 80 non-DS AML controls. The median age at transplantation for DS-AML was 3 years, and almost half of the cohort was in second remission. The 3-year probability of overall survival was only 19%. In multivariate analysis, adjusting for interval from diagnosis to transplantation, risks of relapse (hazard ratio [HR], 2.84; P < .001; 62% versus 37%) and transplant-related mortality (HR, 2.52; P = .04; 24% versus 15%) were significantly higher for DS-AML compared to non-DS AML. Overall mortality risk (HR, 2.86; P < .001; 21% versus 52%) was significantly higher for DS-AML. Both transplant-related mortality and relapse contribute to higher mortality. Excess mortality in DS-AML patients can only effectively be addressed through an international multicenter effort to pilot strategies aimed at lowering both transplant-related mortality and relapse risks